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Assemblin, an essential herpesvirus proteinase. 组装素,一种重要的疱疹病毒蛋白酶。
Pub Date : 1997-05-01
W Gibson, M R Hall

The herpesvirus maturational proteinase, called assemblin, is essential for the production of infectious virus and represents a new molecular target for the development of antivirals. A brief summary of the synthesis, structure, and function of this fascinating enzyme is presented here.

疱疹病毒成熟蛋白酶,称为组装素,对感染性病毒的产生至关重要,代表了抗病毒药物开发的新分子靶点。本文简要介绍了这种令人着迷的酶的合成、结构和功能。
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引用次数: 0
Structure-activity relationships in quinoline Reissert derivatives with HIV-1 reverse transcriptase inhibitory activity. 喹啉Reissert衍生物与HIV-1逆转录酶抑制活性的构效关系。
Pub Date : 1997-04-01
M Font, A Monge, I Ruiz, B Heras

The relationship between the chemical structure and the HIV-1 RT inhibitory activity has been studied for a series of quinoline derivatives. Two methods were used: a standard QSAR analysis, by combining the methods of Hansch and Free-Wilson, and an analysis using quantum chemistry indices as descriptor parameters, by the semiempirical method AM1. The equations obtained lead to the proposal that the activity of the compounds increases, mainly, with the presence of electron-withdrawing substituents in position 6 of the quinoline ring that cause a decrease in the energy from the molecular orbital LUMO. In turn, this fact leads to the proposal that the most important interaction of these compounds with the HIV-1 RT is a charge transfer type interaction, with the quinoline aromatic ring acting as acceptor.

研究了一系列喹啉衍生物的化学结构与HIV-1 RT抑制活性之间的关系。采用两种方法:一种是结合Hansch和Free-Wilson方法的标准QSAR分析,另一种是采用半经验方法AM1的量子化学指标作为描述符参数的分析。得到的方程表明,化合物的活性增加,主要是由于喹啉环6位的吸电子取代基的存在,导致分子轨道LUMO的能量降低。反过来,这一事实导致了这些化合物与HIV-1 RT最重要的相互作用是电荷转移型相互作用的提议,喹啉芳香环作为受体。
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引用次数: 0
Thienocycloheptapyridazines as new muscarinic agents. 硫代环庚吡啶嗪作为新的毒蕈碱剂。
Pub Date : 1997-04-01
D Barlocco, G Cignarella, F Fanelli, B Vitalis, P Matyus, P G De Benedetti

A series of thienocycloheptapyridazines (3aa-dd), structurally related to Minaprine, was synthesized and compounds tested for their affinity towards muscarinic receptors. All of them showed Ki values in the micromolar range towards both the antagonist 3H-QNB and the agonist 3H-OXO-M, thus indicating that they act as antagonists at the muscarinic receptors. Moreover a theoretical study was performed on their interaction behaviour with a three dimensional (3-D) model of the human m1 muscarinic receptor.

合成了一系列与米那普利结构相关的噻吩环庚吡嗪类化合物(3aa-dd),并对其与毒菌碱受体的亲和力进行了测试。它们对拮抗剂3H-QNB和激动剂3H-OXO-M的Ki值均在微摩尔范围内,表明它们对毒蕈碱受体起拮抗剂作用。此外,对他们的相互作用行为进行了理论研究与人类m1毒蕈碱受体的三维(3-D)模型。
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引用次数: 0
Synthesis and evaluation of new Reissert analogs as HIV-1 reverse transcriptase inhibitors. 1. Quinoline and quinoxaline derivatives. 新的Reissert类似物作为HIV-1逆转录酶抑制剂的合成和评价。1. 喹啉和喹啉衍生物。
Pub Date : 1997-04-01
M Font, A Monge, E Alvarez, A Cuartero, M J Losa, M J Fidalgo, C SanMartín, E Nadal, I Ruiz, I Merino, J J Martínez-Irujo, E Alberdi, E Santiago, I Prieto, J J Lasarte, P Sarobe, F Borrás

The synthesis and preliminary evaluation of new quinoline and quinoxaline derivatives (obtained by applying the original Reissert method, conveniently modified) as HIV-1 Reverse Transcriptase (RT) inhibitors are presented in this paper; likewise, the first structure-activity relationships are also proposed. Propyl 2-cyano-1(2H)-quinolin-carboxylate 2e, isopropyl 2-cyano-1 (2H)-quinolincarboxylate 2f, butyl 2-cyano-1 (2H)-quinolincarboxylate 2g and isobutyl 2-cyano-1 (2H)-quinolincarboxylate 2h have been selected as lead compounds. These compounds are active against the HIV-1 RT mutant type P236L (2f, IC50 = 1.2 microM) and present activity as anti-infective agents in HLT41acZ-1IIIB cells, showing no cytotoxicity at the active concentrations.

本文介绍了新型喹啉和喹啉衍生物(采用原始的Reissert方法,方便地进行了修饰)作为HIV-1逆转录酶抑制剂的合成和初步评价;同样,也提出了第一个构效关系。选择2-氰基-1(2H)-喹啉羧酸丙酯2e、2-氰基-1(2H)-喹啉羧酸异丙酯2f、2-氰基-1(2H)-喹啉羧酸丁酯2g和2-氰基-1(2H)-喹啉羧酸异丁酯2H作为先导化合物。这些化合物对HIV-1 RT突变型P236L (2f, IC50 = 1.2微米)具有活性,并且在HLT41acZ-1IIIB细胞中具有抗感染活性,在活性浓度下无细胞毒性。
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引用次数: 0
Synthesis and evaluation of new Reissert analogs as HIV-1 RT inhibitors. 2. Benzo[f]quinoline and pyridine derivatives. 新的Reissert类似物作为HIV-1 RT抑制剂的合成和评价。2. 苯并喹啉和吡啶衍生物。
Pub Date : 1997-04-01
A Monge, E Alvarez, C San Martín, E Nadal, I Ruiz, M Font, J J Martínez-Irujo, E Santiago, I Prieto, J J Lasarte, P Sarobe, F Borrás

The synthesis and preliminary evaluation of new benzo[f]quinoline and pyridine derivatives, obtained by application of the Reissert method and its modifications, as HIV-1 RT inhibitors and anti-infectives are presented. The most active products against HIV-1 RT wild type are the ethyl 2-cyano-1,2-dihydrobenzo[f]quinoline-1-carboxylate 2b, propyl 2-cyano-1,2-dihydrobenzo[f]quinoline-1-carboxylate 2c, and 2-cyano-1-(2'-furoyl)-1,2-dihydrobenzo[f]quinoline 2n, which maintain their activity against the mutant type P236L, resulting inactive against the Y181C type. Using the data previously obtained by our research team for analogous series derived from quinoline as reference, the compounds which have now been obtained present an increase in the cytotoxic character attributable to the introduction of a benzene ring fused with the quinoline base nucleus, as well as a decrease of the activity as HIV-1 RT inhibitors when the quinoline benzenic ring is eliminated.

介绍了利用Reissert方法及其修饰获得的新型苯并[f]喹啉和吡啶衍生物的合成和初步评价,这些衍生物可作为HIV-1 RT抑制剂和抗感染药物。对HIV-1 RT野生型最有效的产物是乙基2-氰基1,2-二氢苯并[f]喹啉-1-羧酸2b,丙基2-氰基1,2-二氢苯并[f]喹啉-1-羧酸2c和2-氰基1-(2′-呋喃基)1,2-二氢苯并[f]喹啉2n,它们对突变型P236L保持活性,对Y181C型无效。利用我们的研究团队之前从喹啉衍生的类似系列中获得的数据作为参考,现在获得的化合物由于引入与喹啉碱基核融合的苯环而呈现出细胞毒性增加的特征,并且当喹啉苯环被消除时,作为HIV-1 RT抑制剂的活性降低。
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引用次数: 0
Effects of adjuvant, dose and carrier pre-sensitisation on the immunisation efficacy of a GnRH analogue. 佐剂、剂量和载体预致敏对GnRH类似物免疫效果的影响。
Pub Date : 1996-12-01
V A Ferro, W H Stimson

A GnRH-neutralising vaccine, with potential applications in the treatment of human sex hormone-dependent disorders, was developed by conjugating GnRH-glycys to tetanus toxoid. An evaluation of adjuvant, dose and carrier pre-sensitisation was made. Male rats immunised with the conjugate, adsorbed onto alum, showed higher anti-GnRH antibody levels and suppressed testosterone concentrations, compared with animals immunised without adjuvant. Conjugate administration in a four injection regime proved to be the most effective in disrupting fertility, as assessed by the degree of lowered testosterone levels and gonadal atrophy. Pre-sensitisation with tetanus toxoid had an initial marked effect on immunisation, observed following 2 drug doses; the pre-sensitised animals showed a lower antibody response to the conjugate than did the non-primed animals. However, as the number of drug doses increased to 4, there was no significant difference between the primed and non-primed animals.

通过将gnrh -甘氨酸与破伤风类毒素结合,开发了一种gnrh -中和疫苗,可能应用于治疗人类性激素依赖性疾病。对佐剂、剂量和载体的预致敏性进行了评价。与未接种佐剂的雄性大鼠相比,接种了这种结合物并吸附在明矾上的雄性大鼠显示出更高的抗gnrh抗体水平和抑制睾丸激素浓度。通过降低睾丸激素水平和性腺萎缩的程度来评估,四次注射的结合给药被证明在破坏生育方面是最有效的。破伤风类毒素预致敏对免疫有最初的显著效果,观察2次药物剂量;预致敏动物对偶联物的抗体反应低于未致敏动物。然而,当药物剂量增加到4次时,启动和未启动的动物之间没有显著差异。
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引用次数: 0
Three-dimensional molecular models of the hMC1R melanocortin receptor: complexes with melanotropin peptide agonists. hMC1R黑素皮质素受体的三维分子模型:与促黑素肽激动剂的复合物。
Pub Date : 1996-12-01
C Haskell-Luevano, T K Sawyer, S Trumpp-Kallmeyer, J A Bikker, C Humblet, I Gantz, V J Hruby

Three-dimensional molecular models of the human melanocortin receptor (hMC1R) have been developed based upon the electron cryo-microscopic structure of bacteriorhodopsin and the electron density footprint of bovine rhodopsin. alpha-Melanocyte-stimulating hormone, Ac-Ser-Tyr-Ser-Met4-Glu-His-Phe7-Arg-Trp-Gly-Lys-Pro-Val-NH2 (alpha-MSH, alpha-melanotropin), and the superpotent, prolonged acting agonists, Ac-Ser-Tyr-Ser-Nle4-Glu-His-DPhe7-Arg-Trp-Gly-Lys-Pro-Val-NH2 (NDP-MSH) and Ac-Nle4-c[Asp5-His6-DPhe7-Arg8-Trp9-Lys10]-NH2 (MTII), have been modeled into the proposed binding sites with specific ligand-receptor interactions identified. The melanotropin sidechain pharmacophores, DPhe7 and Trp9, are proposed to interact with a hydrophobic network of receptor aromatic residues in transmembrane regions 4, 5, 6, and 7. In addition, a hydrophilic network involving the ligand Arg8 and polar receptor residues located in transmembrane regions 2 and 3 were identified. Biological studies on alpha-MSH, NDP-MSH, MTII, and related peptides have been correlated with the proposed hMC1R model in terms of agonism, affinity, and prolongation. Finally, limited MC1R mutagenesis studies comparing alpha-MSH and NDP-MSH are interpreted within the context of the proposed hMC1R models.

基于细菌视紫质的电子冷冻结构和牛视紫质的电子密度足迹,建立了人黑素皮质素受体(hMC1R)的三维分子模型。α -促黑素细胞激素ac - ser - tyrr - ser - met4 - glu - his - phe7 - arg - trp - gly - lys - pro - var -NH2 (α - msh, α -促黑素)和强力长效激动剂ac - ser - tyrr - ser - nle4 - glu - his - dphe7 - arg - trp - gly - lys - pro - var -NH2 (NDP-MSH)和Ac-Nle4-c[Asp5-His6-DPhe7-Arg8-Trp9-Lys10]-NH2 (MTII)已被模型化为所提出的结合位点,并鉴定出特异性配体-受体相互作用。促黑素侧链药物载体DPhe7和Trp9被认为与跨膜区4、5、6和7的受体芳香残基疏水网络相互作用。此外,还鉴定了一个涉及配体Arg8和位于跨膜区2和3的极性受体残基的亲水性网络。关于α - msh、NDP-MSH、MTII和相关肽的生物学研究在激动作用、亲和力和延长性方面与所提出的hMC1R模型相关。最后,比较α - msh和NDP-MSH的有限MC1R突变研究在提出的hMC1R模型的背景下进行了解释。
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引用次数: 0
Evidence of a butterfly-like configuration of structurally diverse allosteric inhibitors of the HIV-1 reverse transcriptase. HIV-1逆转录酶的结构多样的变构抑制剂的蝴蝶样配置的证据。
Pub Date : 1996-12-01
P P Mager

Although many physicochemical properties of chemically diverse nonnucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) differ, there is a common three-dimensional feature. This shape is a rigid butterfly-like configuration which fits well into a sizable internal cavity of the allosteric area of the enzyme. The number of amino acids of the allosteric receptor sites that contribute to NNRTIs binding correlates with the degree of the butterfly-like shape. It seems that molecular rigidity of the butterfly-like shape, the drug affinity and the probability of resistance development are closely related.

尽管化学上不同的HIV-1逆转录酶(NNRTIs)非核苷抑制剂的许多物理化学性质不同,但有一个共同的三维特征。这种形状是一种刚性的蝴蝶状结构,非常适合于酶的变构区域的相当大的内部腔。参与NNRTIs结合的变构受体位点的氨基酸数量与蝴蝶形状的程度相关。看来,蝴蝶状分子的刚性、药物亲和力和耐药发生的概率密切相关。
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引用次数: 0
Molecular simulation of the folding patterns of the omega-loop (Tyr181 to Tyr188) of HIV-1 reverse transcriptase. HIV-1逆转录酶- ω -环(Tyr181至Tyr188)折叠模式的分子模拟。
Pub Date : 1996-12-01
P P Mager

A large, highly hydrophilic and constrained omega-loop was dissected from the allosteric area of HIV-1 reverse transcriptase (segment Tyr181 to Tyr188). The loop contains two amino acids (Asp185, Asp186) of the catalytic aspartyl triad (Asp110, Asp185, Asp186) and two amino acids (Tyr181, Tyr188) of the nonnucleoside RT inhibitor (NNRTI) binding sites. Hydrogen-bonding forces between the two folded peptide chains play the greatest role in holding the two chains together and in specifying the folding patterns. The treatment of solvents as dielectric continuums surrounding the AMBER force field model has shown changes in conformation but these changes were not dramatically because the omega-loop shape was completely maintained.

从HIV-1逆转录酶(片段Tyr181至Tyr188)的变抑区解剖出一个大的、高度亲水的限制性ω -环。该环含有催化天门冬氨酸三联体(Asp110、Asp185、Asp186)的两个氨基酸(Asp185、Asp186)和非核苷类RT抑制剂(NNRTI)结合位点的两个氨基酸(Tyr181、Tyr188)。两条折叠肽链之间的氢键力在将两条肽链固定在一起和确定折叠模式方面起着最大的作用。在AMBER力场模型周围,溶剂作为介质连续体的处理显示出构象的变化,但这些变化并不明显,因为ω -环形状完全保持不变。
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引用次数: 0
A hydrophilic omega-loop (Tyr181 to Tyr188) in the nonsubstrate binding area of HIV-1 reverse transcriptase. HIV-1逆转录酶非底物结合区的亲水性ω -环(Tyr181至Tyr188)。
Pub Date : 1996-12-01
P P Mager, H Walther

Using the molecular "cloud" of the HIV-1 reverse transcriptase (RT) as starting point, the peptide backbone of the polymerase subunit was visualized by molecular modelling. Then, the two subregions 98-106 and 179-190 of the allosteric area were "isolated". From the latter subregion, the Tyr181 to Tyr188 segment containing two amino acids (Asp185, Asp186) of the catalytic aspartyl triad and two amino acids (Tyr181, Tyr188) of the nonnucleoside RT inhibitor (NNRTI) binding sites, was excised. It was shown that the segment has a omega-like loop configuration which is highly hydrophilic. The two phenolic side chains of Tyr181 and Tyr188 represent the lipophilic "horizontal axes" of the omega-loop shape. The relative rigidity of the omega-loop is mainly based on a hydrogen bond between the peptide CO of Tyr181 and the peptide NH of Tyr188. Solvation in water increases the number of intramolecular hydrogen bonds. Therefore, desolvation is one of the conditions of binding with NNRTIs. Site-directed mutagenesis affects the hydrophilicity of the omega-loop while steric features are less influenced.

以HIV-1逆转录酶(RT)的分子“云”为起点,通过分子建模可视化了聚合酶亚基的肽骨架。然后对变构区98 ~ 106和179 ~ 190两个分区进行“隔离”。从后一个亚区,Tyr181到Tyr188段包含催化天门冬氨酸三联体的两个氨基酸(Asp185、Asp186)和非核苷类RT抑制剂(NNRTI)结合位点的两个氨基酸(Tyr181、Tyr188)。结果表明,该片段具有高度亲水性的-类环构型。Tyr181和Tyr188的两个酚侧链代表ω -环形状的亲脂性“水平轴”。ω -环的相对刚性主要基于Tyr181的肽CO和Tyr188的肽NH之间的氢键。在水中的溶剂化增加了分子内氢键的数目。因此,脱溶是与NNRTIs结合的条件之一。定点诱变会影响-环的亲水性,而位阻特性受影响较小。
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引用次数: 0
期刊
Drug design and discovery
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